The treatment of schizophrenia remains one of the major challenges of modern-day medicine. Even incremental advances in the safe and effective use of currently available treatments can have a major impact on the lives of schizophrenic individuals and their families. Reducing rates of relapse and rehospitalization by as little as 10 percent per year can have enormous public health implications. (J. M. Kane, Special Report: Schizophrenia, 1987, National Institute of Mental Health, in: Schizophrenia Bull., 13:133-156, 1987).
It is estimated that about 2 million Americans suffer from classical schizophrenia. Approximately 200,000 to 400,000 (10-20 percent) of these schizophrenic patients do not respond to treatment with traditional neuroleptics (antipsychotic drugs) and are classified as therapy-resistant schizophrenics.
Data gathered from maintenance medication trials indicate that 20 to 30 percent of patients initially responsive to antipsychotic drugs may relapse during the first year or two of maintenance drug treatment. A proportion of these relapsed patients may contribute to the number of patients refractory to treatment (J. M. Kane, J. Lieberman, Psychopharmacology. the Third Generation of Progress, 1987 Ravin Press, ed., H. Y. Meltzer, pp. 1103-1109).
The term "treatment-(or therapy-)-resistant" schizophrenia used in this context describes a particular illness generally understood by a physician skilled in the art. The treatment-resistant schizophrenic patient may be minimally defined as a patient with schizophrenia without marked symptomatic relief from two treatment periods with two neuroleptic agents from different chemical classes. Clinical research has suggested that neuroleptic-resistant patients suffer from an illness which is characterized by pharmacodynamic, psychological, and physiological properties which differ from those of the neuroleptic-responsive patient. Thus, therapeutic agents known to be effective in the treatment of schizophrenia are not useful in the treatment of therapy-resistant schizophrenia.
In general, the phenothiazines (e.g., chloropromazine) and the butyrophenones (e.g., haloperiodol) constitute the classical neuroleptics used in the treatment of schizophrenia to which the therapy-resistant patient does not respond. More effective pharmacotherapy for the treatment of therapy-resistant schizophrenia has not been developed in the more than three decades since the introduction of the first effective neuroleptic drugs.
Thus far, the only drug approved for clinical use in treating therapy-resistant schizophrenic patients is clozapine, which was approved by the FDA in September 1989 for this particular use. Clozapine, belonging to the chemical class of dibenzodiazepines, was developed in 1966. Agranulocytosis, a potentially fatal drop in white blood cells, is a very dangerous side effect which occurs in 1-2 percent of clozapine-treated patients. Because of this harmful side effect, clozapine has not been used in many countries and for a time was withdrawn from clinical research (H. Hippius, Psycopharmacology, 1989, Supplement to Vol. 99 pp. S3-S5; R. Grohmann et. al., Psycopharmacology, 1989, Supplement to Vol. 99, pp. S101-S104).
The fact that clozapine now has been accepted by the FDA for treating therapy-resistant schizophrenic patients despite the occurrence of such serious adverse side effects, underlines the urgent need for alternative drugs to treat the therapy-resistant schizophrenic patients. Moreover, there is a need for a method of treating these patients with a drug that does not give rise to potentially fatal adverse reactions.